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A Phase Ib Study of Alpelisib (BYL719), a PI3K?-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.


ABSTRACT: PURPOSE:Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110?, has shown synergistic antitumor activity with endocrine therapy against ER+/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER+ breast cancer refractory to endocrine therapy. EXPERIMENTAL DESIGN:Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing. RESULTS:Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ?6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ?12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. ©2016 AACR.

SUBMITTER: Mayer IA 

PROVIDER: S-EPMC5085926 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.

Mayer Ingrid A IA   Abramson Vandana G VG   Formisano Luigi L   Balko Justin M JM   Estrada Mónica V MV   Sanders Melinda E ME   Juric Dejan D   Solit David D   Berger Michael F MF   Won Helen H HH   Li Yisheng Y   Cantley Lewis C LC   Winer Eric E   Arteaga Carlos L CL  

Clinical cancer research : an official journal of the American Association for Cancer Research 20160428 1


<h4>Purpose</h4>Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER<sup>+</sup>/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER<sup>+</sup> breast cancer refractory to endocrine therapy.<h4>Experimental design</h4>Twenty-six patients received letrozole and alpelisib dail  ...[more]

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